This Application is a 371 of PCT/GB97/03525 filed Dec. 23, 1987
This invention relates to the treatment of relief of fecal incontinence and anal itch (pruritis ani), particularly for patients who have had a major bowel resection and reanastomosis.
Anal or fecal incontinence is the inability to voluntarily control the passage of feces or gas through the anus. It may occur either as fecal soiling or as rare episodes of incontinence for gas or watery stools. It is a very distressing condition that can result in self-inflicted social isolation and despair.
Conventional treatments for fecal incontinence include drug therapy to improve stool consistency, such as morphine, loperamide and codeine phosphate to reduce gut motility, and laxatives to soften stools and relieve constipation. Biofeedback training is another treatment which involves muscle strengthening exercises to improve anal canal resting pressure, and squeeze pressure, and to teach symmetry of anal canal function. The most common form of treatment however, is surgical repair, such as the creation of a neo-sphincter which involves grafting on muscle from other parts of the anus, or a colostomy. (Gastroenterology in Practice, Summer 1995, p18-21; Dig Dis 1990; 8:179-188; and The New England Journal of Medicine, April 1992, p1002-1004). In mild cases of anal leakage, the patient will often try and plug the anus with a ball of cotton wall.
In Gut, 1991, 32, p. 345-346 it was reported that two thirds of patients with idiopathic faecal incontinence had a decreased anal resting pressure resulting from an abnormal internal sphincter function. In many incontinent patients, the internal anal sphincter was found to be abnormally thin, while others had an external anal sphincter defect.
It has also been reported that in vitro contractile response of the internal anal sphincter to noradrenaline is decreased in incontinence, (Br. J. Surg. 1992, vol 79, August, p829-832; Digestive Diseases and Sciences, vol 38, no. 11, November 1993, p1961-1969). A further discussion of the innervation and control of the internal anal sphincter and drugs which can increase or decrease the normal anal resting pressure, is discussed in the text book Coloproctology and the Pelvic Floor (Butterworths), second edition, 1992, at chapter 3 p37-53; Automic Control of Internal Anal Sphincter; and Journal of Clinical Investigation 1990, 86: p424-429.
In Surgery 1990; 107: p311-315 sodium valproate was found to be useful in the treatment of minor incontinence after ileoanal anastomosis.
It has now surprisingly been found that fecal incontinence and anal itch can be resolved by treatment with xcex1 adrenergic agonists, nitric oxide synthase inhibitors, prostaglandins F2xcex1, dopamine, morphine, xcex2-blockers such as propranolol, and 5xe2x80x94Hydroxytryptamine (5xe2x80x94HT).
This is surprising since it was always thought that once an anal sphincter began functioning abnormally, the patient would require major surgery.
In this way the anal leakage is reduced or eliminated without the patient having to undergo major surgery.
Accordingly in a first aspect of the invention there is provided method for the treatment or prophylaxis of fecal incontinence or anal itch by topical application in and/or around the anal canal of a patient, a therapeutically active amount of a physiologically active agent selected from an xcex1 adrenergic agonist, nitric oxide synthase inhibitor, prostaglandin F2xcex1, dopamine, morphine, xcex2-blockers, and 5xe2x80x94Hydroxytryptamine
The agents of the invention appear to at least partially treat the incontinence by increasing the resting pressure of the internal anal sphincter.
Preferred agents are al adrenergic agonists, nitric oxide synthase inhibitors, and prostaglandin F2xcex1.
Examples of suitable xcex11 adrenergic agonists are norxe2x80x94adrenalin, methoxamine, but particularly preferred is phenylephrine.
Examples of suitable F2xcex1prostaglandin are dinoprost and carboprost.
Examples of suitable NO synthase inhibitors are NGxe2x80x94monomethyl-L-arginine (L-NMMA), and NGxe2x80x94nitro-L-arginine methyl ester (L-NAME).
The medicament can contain a single active agent or a combination of any of the above active agents.
Nitric Oxide (NO) synthase inhibitors such as LNMMA have previously been suggested for the therapeutic treatment of septic shock.
The prostaglandins, along with thromboxanes and leukotrienes are all derived from 20-carbon polyunsaturated fatty acids an are collectively termed eicosanoids. F2xcex1prostaglandins derived in vivo from the endoperoxide prostaglandin H2 which turn derived from leukotrienes. Clinically, F2xcex1prostaglandin preparations such as dinoprost and carboprost are used as uterine stimulants in the termination of pregnancy, missed abortion or the induction of labor.
Phenylephrine (an xcex11 adrenergic agonist) is used as a mydriatic in ophthalmology, and as a decongestant, for example, in cold and flu remedies.
However there has been no suggestion to the iventors knowledge of using any of these active agents to treat fecal incontinence or anal itch.
As used herein xe2x80x9cfecal incontinencexe2x80x9d includes all types of anal leakage from minor leakage or xe2x80x98spottingxe2x80x99 through moderate leakage, to major instances of faecal incontinence, and includes neurogenic, active, urge and passive incontinence.
More particularly the class of incontinent patients who will benefit most from the present invention are those with idiopathic incontinence and those whose incontinence is at least partly due to a weakness of either the internal or external anal sphincter, especially those with a normal or low maximum anal pressure and a structurally intact internal anal sphincter muscle, such as with an abnormally thin sphincter. However patients with minor structural damage such as a fragmented sphincter would still benefit from the invention. Not only incontinent patients with a damaged or abnormal internal sphincter can be treated, but also patients with a damaged or abnormal external sphincter since the increase in the internal anal resting tone induced by the invention will compensate for a poorly functioning external sphincter.
Another class of patients who particularly benefit from the invention are post-surgical patients who have had major bowel resection and reanastomosis. For example patients with ileoanal pouch (restorative proctocolectomy), coloanal (with or without colonic pouch) anostomosis, lower anterior resection, and colectomy with ileorectal anastomosis.
The damage to the sphincter could be caused by trauma, such as experienced in child birth, surgical operations, or road traffic accidents. Furthermore it is also believed that incontinence caused by primary internal anal degeneration can also be relieved by the invention.
Anal leakage also often leads to pruritis of the anus and therefore by reducing or eliminating the leakage, the pruritis or anal itch is also relieved or prevented.
Furthermore, as a result of the increased anal resting pressure, the patient no longer has the discomfort of distended anal sphincter muscles.
Physiologically acceptable salts of the above active compounds are also within the scope of the invention. Suitable salts include those formed with both organic and inorganic acids, such as those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic and isethionic acids.
By salt we also mean to include any complex or pseudo salt wherein the active agent (such as phenylephrine) is associated with, for example, a derivative to an organic or inorganic acid.
Prodrugs and any other bioprecursor which are converted in vivo to the active agents (such as phenylephrine) are also within the scope of the invention.
A particularly preferred salt of phenylephrine is the hydrochloride salt.
Although the medicament can be administered, for example, orally or intravenously to systemically treat the faecal incontinence, it is preferred that the incontinence is treated by local or topical application of the medicament in and/or around the anal canal of the incontinent patient. Alternatively the agents of the invention can be locally injected directly into the internal anal sphincter. In both locally and systemically acting compositions, at least a pharmacologically acceptable carrier will be present along with the active.
Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions.
Pharmaceutical composition adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the. intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, immediately prior to use.
Pharmaceutical compositions adapted for topical administration in and/or around the anal canal may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, foam, oils, suppositories or enemas.
The topical compositions can comprise emulsifiers, preservatives, buffering agents and anti-oxidants. Preferably the compositions also comprise steroids and locally acting anaesthetics.
The dosage of the composition will depend on the severity of the incontinence, the route of administration, the age, weight and condition of the patient being treated. For example a suitable daily dosage of medicament, such as phenylephrine, based on a 70 kg patient with moderate faecal incontinence would be 40 mg/day to 2000 mg/day, such as 40 to 400 mg or 40 to 200 mg/day, preferably at a lower limit of at least 50 mg/day.
For rectally administered topical compositions such as phenylephrine, the percentage of active is preferably at least 5% w/w, more preferably at least 10% w/w, and advantageously up to about 50% w/w of the composition. The dosage of active such as phenylephrine is preferably at least 40 mg per 0.5 ml of composition, more preferably at least 50 mg per 0.5 ml of composition, such as up to about 250 mg/ 0.5 ml. In fact, early investigations indicate that higher dosages will be more beneficial because of the subnormal sensitivity of the anal sphincter. The total amount of active present in a topical composition (such as a tube) is suitably from 40 to 5000 mg, such as 40 mg to 1000 mg, or 40 to 500 mg of active. The topical composition should be applied 1 to 6 times daily, such as 3 times daily until there is a relief from the incontinence.
The topical composition may comprise skin penetrating agents, particularly the sulphoxides, such as dimethyl sulphoxide (DMSO) preferably at 25% to 50% w/w. Amides, (DMA, DMF) pyrrolidones, organic solvents, laurocaprom (AZONE) and calcium thioglycollate are suitable alternative penetrants. The composition may also optionally contains a polyacrylic acid derivative, more particularly a carbomer. This would both act as a skin hydrating agent to aid penetration of the drug, but also an emulsifying agent. The carbomer will help emulsify the DMSO, thereby mitigating skin irritation and providing enhanced skin hydration. Propylene glycol may also be present in the composition to soften the skin, increase thermodynamic potential and aid skin penetration by the DMSO and thus the drug. The final pH of the composition is advantageously pH 3.5 to 4.5.